You can change how much you exercise. You can change your diet. But you can’t
change your parents. And, unfortunately, many common diseases have a genetic
Dr. Richard Lifton, Howard Hughes Medical Institute investigator and Sterling
Professor and chair of genetics, has done pioneering research on the genetics
of cardiovascular disease, osteoporosis and renal disease, among other
disorders. His research combines traditional family studies with the most current
genomics’ tools of analysis.
Lifton is a genetics detective. He looks for hereditary extremes — very,
very dense bones, for instance — to help people with a problem at the
other extreme, such as the frail bones of osteoporosis.
This month he was awarded the Wiley Prize in Biomedical Sciences for his discovery
of the genes that cause many forms of high and low blood pressure. (See related
In a recent netcast interview conducted by Colleen Shaddox, Lifton explained
what led him to study the complex problem of hypertension, as well as what
he sees ahead in genetics research. The following is an edited excerpt from
Traditionally scientists looked for a single gene that causes a disease, but
you wanted to study hypertension, which is much more complex. Why not study
a more cooperative disease?
This is one of the big challenges in science, to figure out how to have the
most impact on the most important problems. Twenty years ago tools were starting
to emerge from the human genome project that gave us hope that we would be
able to start understanding not just rare diseases that are in the field of,
typically, medical genetics, but that we might start having an impact on common
diseases too. I was attracted to cardiovascular disease initially because it
is the single largest cause of death worldwide. In particular, I was interested
in investigating hypertension, a major risk factor for cardiovascular disease
that affects one billion people around the world.
What was your strategy?
At the time, it was recognized that blood pressure is not like simple disorders
where there are likely to be single genes that have big effects that are
common in the population. So we took a page from simple studies in model
organisms. For decades we’ve done experiments in model organisms like
fruit flies where we’ve taken complex problems and done mutagenesis
on the flies to make mutations, and then look at which mutations have really
large effects on traits that we’re interested in. We obviously can’t
do mutagenesis in humans, but we can take advantage of the fact that there
are 13 billion copies of the human genome walking around the planet—six-and-a-half
billion people with two copies of each gene.
We reasoned that if we could cast our net broadly enough, we ought to be able
to identify extreme outliers in the population who have either extraordinarily
high blood pressure or life threatening blood pressure at very young ages.
If these turn out to be due to mutations in single genes, we ought to be able
to identify the underlying mutations that cause these traits.
And when you gathered a large enough sample of these extraordinary people,
what did you learn?
I think the most impressive finding is that, despite the incredible complexity
of blood pressure regulation, the mutations that we’ve identified — and
we now have mutations in 10 genes that will dramatically raise blood pressure
and another 10 that will dramatically lower blood pressure — that these
aren’t distributed throughout the physiologic landscape, but instead
they converge on a single final common pathway and that is the pathway that
regulates salt re-absorption by the kidney.
How has this changed the way physicians treat high blood pressure?
Our work has demonstrated the fundamental importance of reduction in salt balance
as a primary goal of therapy. The national recommendations now reflect this
in recommending salt reduction as a key goal of therapy. In addition, our
studies have identified several therapeutic targets that might lead to improved
treatment of this common disease; these are under development.
Interestingly, we also found that patients who have an inherited defect that
causes them to lose salt all the time also have a very powerful behavioral
drive to eat more salt. Children who can’t hang onto salt normally in
the kidney will tell you fascinating things, like their favorite beverage is
pickle juice, or they like to eat lemons covered in salt. So, extrapolating
these observations to the treatment of patients with hypertension, we now recognize
that in addition to giving them a single agent that reduces salt balance, we
need to give them agents that reduce the drive to eat more salt as well.
Because we’re talking about a hereditary disorder, does that make patients
particularly eager to collaborate with you?
Absolutely. I think this is one of the lessons that we have learned time and
again. The part that has impressed me greatly is not that the patients expect
there is going to be any direct benefit to them, but they recognize that their
families have problems that could advance the understanding of a particular
disorder and might ultimately improve healthcare in the future. We quite commonly
are invited to family reunions to study family members.
You’ve met some fascinating people. Talk about the man who couldn’t
This patient came to our attention because of a motor vehicle accident on a
Saturday night and a very astute resident at the hospital. If you have a motor
vehicle accident and you’re brought to the emergency room, you virtually
always have x-rays taken of your cervical spine to rule out a life-threatening
fracture. The resident saw there was no fracture, but he was very concerned
because the patient’s bones appeared to be the densest he had ever seen
and he was concerned that he might have some serious underlying disease.
(Dr.) Karl Insogna at the Bone Center at Yale measured the patient’s
bone density and said only one in many billion people would have such high
bone density. The patient had no complaints at all except that he and many
of his family members sank when they tried to swim. We found their bodies don’t
simply slow down the loss of bone, they actually are making more bone all the
Lynn Boyden in the laboratory identified the underlying mutation, which identified
a new signaling pathway in the normal regulation of bone formation. This finding
has focused further investigation in the pharmaceutical industry to attempt
to develop new medicines that could mimic the effect of these mutations. The
goal is to increase the rate of deposition of bone to prevent the development
of osteoporosis and to reverse its effects.
You are increasingly looking at renal disease. Please explain why this is
Kidney disease is where we were with high blood pressure 10 years ago. There
are hundreds of thousands of Americans on dialysis now because their kidneys
have failed. Yet we know very little about the primary causes. We know there
are risk factors: diabetes, high blood pressure and inherited contributions.
What has changed from when we started in high blood pressure is the tools have
gotten progressively better as time has gone on. The complete sequence of the
human genome has been finished; we now know all of the common variations in
the human genome sequence. Now we can start to look both for common variants
that contribute to kidney disease, as well as rare variants that contribute
to this trait. I’m quite optimistic that in the next several years we
will start to identify some of the inherited contributions to this trait and
that these will ultimately lead to new therapies that will prevent this disease.
How do you think genetics is going to fundamentally change medicine within
the next decade?
If you look at where we started 10 years ago and where we’ve come in
just that time period, I think it’s safe to say that virtually every
area of medicine has been drastically changed in its fundamental understanding
of disease pathogenesis. This cuts across every disease, from Alzheimer’s
disease, to diabetes, to high blood pressure, to cholesterol, to cancer. We
have made fundamental advances in understanding basic pathways that are contributing
to disease predisposition, but we’ve been doing this with extremely blunt
tools. We have been able to find the genes that have whopping effects in rare
individuals, but our tools are now getting sharp enough to enable us to start
to identify what are the genes that are predisposing to disease in the general
I think there will be two general contributions emerging over the next five
years: one, starting already to happen, will be finding the common variations
that have fairly modest — but on the population level, substantial — contributions
to the risk of disease. And then I think increasingly over the next several
years we will have the ability to not just look at a large number of common
variants in the general population, but to actually be able to re-sequence
all of the genes in a single individual or in cohorts of individuals. This
will really start to have a major impact on the way we both diagnose predisposition
as well as start to think about how can we actually impact the treatment of
There is a very big gap between knowing the cause of disease and being able
to treat it. What genetics now has the promise to do is to tell you not just
that this is something that might work, but it’s something that has an
extremely high likelihood of success and will not fail because of adverse therapeutic
effect, something that has been a major problem in the pharmaceutical industry
as well. This holds enormous process for streamlining the process of disease
understanding, leading all the way to new therapeutics.
T H I SW E E K ' SS T O R I E S
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